Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2High receptor

• Published in: Synapse (New York, N.Y.) Vol. 63; no. 10; pp. 935 - 939
• Main Authors: Seeman, Philip, Guan, Hong-Chang
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2009
• Subjects: D2High receptor; DA partial agonist; glutamate agonist; LY404; LY404,039; psychosis; schizophrenia
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.20704

The glutamate agonist LY404,039 has been used to treat schizophrenia. Because all currently used antipsychotics act on dopamine receptors, it was decided to examine whether this glutamate agonist also had an affinity for dopamine D2 receptors in vitro. The present data show that LY404,039 inhibited the binding of [3H]domperidone and [3H](+)PHNO by 15.5 ± 1.5% to the high‐affinity state, D2High, of cloned dopamine D2Long receptors and rat striatal tissue with dissociation constants of between 8.2 and 12.6 nM. This high‐affinity component of LY404,039 on the binding of [3H]domperidone was inhibited by the presence of guanine nucleotide, indicating an agonist action of the drug at D2High. LY404,039 also stimulated the incorporation of [35S]GTP‐γ‐S into D2Long receptors (EC50% = 80 ± 15 nM) over the same range of concentrations as occurred for the inhibition of [3H]domperidone by LY404,039 at D2High (IC50%High = 50 ± 10 nM). A possible clinical antipsychotic action of LY404,039 may depend on the combined stimulation of glutamate receptors and a partial dopamine agonist action that would interfere with neurotransmission at D2High receptors. Synapse 63:935–939, 2009. © 2009 Wiley‐Liss, Inc.